2-bromo-9alpha-fluoro-delta1-pregnene-11beta, 17alpha, 21-triol-3, 20-dione and 21 esters thereof



United States Patent 2-BROMO-9a-FLUORO-A -PREGNENE-11fi,17a,2l- TRIOL-3,20-DIONE AND 21 ESTERS'THEREOF.

Josef Fried, New Brunswick, N. J., assignor to 01in Mathieson Chemical Corporation, ,New York, N. Y., a corporation of Virginia- No Drawing. Original application June 28, 1955, Serial No. 518,680. Divided and'this application October 17, 1957, Serial No. 694,471

3 Claims. (Cl. 260-39745) This application is a division of my parent application, Serial No. 518,680, filed June 28, 1955, and a continuation-in-part of my patent application, Serial No. 489,769, filed February 21, 1955, which in turn is a continuation-in-part of my parent applications, Serial No. 417,489, filed March 10, 1954, and Serial No. 343,243, filed March 18,1953, now abandoned.

This invention relates to synthesis of valuable steroids.

In my parent application, Serial No. 489,769, I disclose a process for converting 2,4-dibromo-9a-fluoroallopregnane 11fi,l7oz,21 triol 3,20 dione and 21 esters thereof (particularly the ZI-acetate) to the following: 9a-fluoro-A -pregnadiene-l1B, 17oz,21-triOl-3,2O dione; 9a-fiuoro-A -pregnadiene-llfl,17u,21-triol 3,20 dione; and 21-esters (e. g. 21-acetates) thereof. This conversion is most readily elfected by heating the dibromide with an organic base, such as lower alkylated pyridine (e. g. collidine) the two resulting steroids then being separated from the reaction mixture by chromatography.

I have now discovered that if this conversion is done on a large scale, three additional hitherto undisclosed, physiologically active steroids are produced. These three newly discovered steroids are: 2-bromo-9a-fluoro- A -pregnene-11fl,17a,21 triol 3,20 dione and 21-esters thereof; 2-bromo-9a-fluorohydrocortisone and 21-esters thereof; and an isomer of 9a-fiuoro-A -pregnadiene- 115,l7a,2l-triol-3,20-dione and 2l-esters thereof. Among the utilizable esterifying acids may be mentioned the carboxylic acids, especially hydrocarbon carboxylic acids containing less than ten carbon atoms as exemplified by the lower alkanoic acids (e. g. acetic, propionic, butyric and enanthic), aromatic hydrocarbon carboxylic acid (e. g. benzoic acid), and hydrocarbon aralkanoic acids (e. g. phenylacetic and fi-phenylpropionic acid). The five steroid products are separated by chromatography, as more fully detailed in the following example.

If a 2l-ester is initially formed, it can be hydrolized to the free 2l-ol by treatment with a base, such as an alkali metal salt of carbonic acid (e. g. potassium carbonate). Furthermore, the llfi-hydroxy steroids can be oxidized with a hexavalent chromium compound (e. g. chromic acid) in an organic acid (e. g. acetic acid) to the corresponding ll-keto derivatives.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 (a) 2-br0mo-9a-fluoro-A -pregnene-l I 5,] 70:,21 -triol- 3,20-dione 21-acetate A solution of 20.7 g. of crude 2,4-dibromo-9a-fiuoroallopregnane-l1B,17a,21-triol-3,20-dione 2l-acetate in 150 ml. of collidine is refluxed under nitrogen for 45 minutes. Concentration of the reaction mixture in high vacuum results in a syrupy residue, which is taken up in chloroform and extracted with dilute sulfuric acid to remove all residual collidine. The chloroform extract is then washed with dilute sodium bicarbonate and water and evaporated to. dryness:..in-vacuo. Theresidue, (about 11.7 g.) is dissolved in -ml. of chloroform and 300 ml. of benzene and. chromatographedon-ISO g. of sulfuric acid-washed alumina. Elution ofthe column with 1 part chloroform and 3 partsbenzene (5,000 ml.) affords 2-bromo-9a-fluoro-A -pregnene 11fl,17a,21 triol- 3,20'dione 21-acetate (about' 1.1 g. crude) which after recrystallization from-'95% alcohol has the following properties: M. P-. aboubl84-1-85 after meltingand resolidification at about lid-139?; [a.l-, -l-79. (c. 0.99 in CHCl A31, 250 m (5:8000); AH 2.85;,

2.98;; (OH), 5.80 (acetylated side chain),

5.90 5.98 624 (2-bromo-A 3-ketone) Analysis.Calcd. for CQ3H3OOBFBI'CQH5OHZ C, H, 6.63; Br, 14.59; OC H 8.23. Found: C, 54.48; H, 6.78; Br, 14.50; OC H ,7.57.

2-bromo-9a-fluoro-A -pregnene-11p,17u,21 triol 3,20- dione 21-acetate is a mineralocorticoid which can be used in the same manner as desoxycorticosterone in the treatment of Addisons disease or adrenal insufliciencies.

(b) 2-br0mo 9a fluorohydrocortisone 21 acetate (2- brom0-9a,-fluor0-A -pregnene-113,1 7a,21 triol 3,20- dione 2.1-acetate) Further elution of the column with 1 part chloroform and 2 parts benzene (2000 ml.) furnishes 2-bromo-9afluoro-M-pregnened1B,17a,21-triol-3,20-dione 21-acetate (about 750 mg. crude), which after crystallization from 95% alcohol has the following properties: M. P. about 174-175; [a] -|-136 (c. 0.80 in CHCl 1:2, 242 m (e=12,200); ASE? 2.85-2.95p (OH),

5.7 81;, 5.85;; (acetylated side chain),

5.94;, 6.15; (2-bromo-A -3-ketone) Analysis.-Calcd. for c,,H,,o,FBr: C, 55.09; H, 6.17; Br, 15.96. Found: C, 55.70; H, 6.30; Br, 15.16.

2-bromo-9m-fluorohydrocortisone Z-acetate is about as active as hydrocortisone in the rat liver glycogen assay and hence is a glucocorticoid which can be used instead of hydrocortisone or cortisone in the treatment of rheumatoid arthritis or dermatomyositis. It is further useful as an intermediate in the preparation of 9a-fiuoro-A pregnadiene-l1B,17a,2l-triol 3,20 dione ZI-acetate and 9a-fluoro-A -pregnadiene-11B,l7a,2l-triol-3,20-dione 21- acetate by renewed treatment with boiling collidine.

(c) 6-dehydro-9a-fluorohydrocortisone 21 -acetate and I dehya'ro-Qa-fluorohydrocortisone ZI-acetate (9a-fluoro- A -pregnadiene-1119,17a,21-tri0l-3,20-dione 21 acetate and 9a-flu0n0-A -pregnadiene-11,6,17a,21 triol 3,20- dione 21 -acetate) Continued elution with chloroform containing 5% acetone (10,000 ml.) elutes 6-dehydro-9a-fluorohydrocortisone acetate (about 2.1 g. crude), which after recrystallization from acetone-hexane has the following properties: M. P. about 216-217"; [a] +123 (c. 0.36 in 95% alcohol)+ (c. 0.36 in CHCl Ag}, 281 m (e=23,000) [see Serial No. 489,769]

6-dehydro-9a-fluorohydrocortisone acetate is followed on the column [same eluant as above (5,000 ml.) and chloroform containing 7.5% acetone (12,000 ml.)] by 1- dehydro-9wfluorohydrocortisone acetate (about 700 mg. crude), which after recrystallization from acetone-hexane (2 crystalline forms, needles which spontaneously change into prisms) has the following properties: M. P. about 243-245 [m] +99 (c. 0.78 in acetone);

M11, 238 m (15,000). [See Serial No. 489,769]

(a!) Isomer of I-kiehydro-9e-fluorohydrocortisone 21 acetate? Final elution of the column with 10% acetone in chloroform (7,000 ml.) followed by 15% acetone in chloroform (4,500 ml.) produces an isomer of l-dehydro- 9m-fluorohydrocortisone acetate which after crystallization from alcohol has the following properties: M. P. about 271-272, [u] +73 (c. 0.59 in alcohol) M3 237 my (6 15,200); km 3.001;, .t 5.75 5.92p, 6.04:,u, 6.18 6.24

The invention may be otherwise variously embodied within the scope of the appended claims.

I claim:

1. A steroid selected from the group consisting of 2- bromo-9oz-fluoro-A pregnene 11fi,17cz,21 triol 3,20- dione and 21-esters thereof with a hydrocarbon carboxylic acid of less than 10 carbon atoms.

2. A 21-ester of 2-bromo-9a-fluoro-A -pregnene-11,6- 17a,21-triol-3,20-dione with a hydrocarbon carboxylic acid of less than ten carbon atoms.

3. The ester of claim 2 wherein the carboxylic acid is acetic acid.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,848,465 August 19, 19585 Josef Fried It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Signed and sealed this 18th day of November 19580 Attest;

KARL H. -AXIJIJIE Attesting Oflicer ROBERT C. WATSON Commissioner of Patents 

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF 2BROMO-9A-FLUORO-$1 - PREGNENE - 11B,17A,21 - TRIOL - 3,20DIONE AND 21-ESTERS THEREOF WITH A HYDROCARBON CARBOXYLIC ACID OF LESS THAN 10 CARBON ATOMS. 